ABSTRACT Cerebral malaria (CM) and severe malarial anemia (SMA) are estimated to affect >500,000 children and 1-5 million children, respectively, in sub-Saharan Africa annually. Our research studies in Ugandan children have demonstrated that CM and SMA are associated with significant neurobehavioral impairment (NBI). Our data suggest that: 1) the pathogenesis of CM and SMA-related NBI differs; 2) CM and SMA lead to greater NBI than other forms of severe malaria; 3) NBI persists for at least 2 years; and 4) several host immune response factors are associated with NBI in children ?5 years of age but not in children <5 years of age. Retrospective studies suggest NBI is present up to 9 years after CM, but there are no prospective studies on the duration of NBI after CM beyond 2 years, or on chronic cognitive or mental health sequelae of other forms of severe malaria such as SMA. We prospectively enrolled >1,700 children in 3 studies that assessed NB sequelae of severe malaria. These studies provide a unique cohort in which to assess the effects of the 5 major forms of severe malaria on long-term cognition and mental health. We propose to study ~1,100 of these children 4-20 years after their severe malaria episode, to answer 3 key questions: 1) Do NB sequelae of severe malaria persist through childhood into adulthood, and do they differ by form of severe malaria? 2) What are the long- term functional and economic costs of these sequelae? 3) What are the risk factors for long-term NBI, and are some factors identifiable only as children grow older and acquire specific cognitive skills? The study?s central hypotheses are that: 1) NBI after severe malaria differs by type of severe malaria and age at episode; 2) these impairments have significant social, economic and quality of life costs; and 3) risk factors for impairment may become apparent only after 5 years of age. Our study has 3 Aims. Aim 1 is to establish the duration and age- specific manifestations of neurobehavioral sequelae of severe malaria from childhood to early adulthood. Aim 2 is to determine the functional and economic costs of neurobehavioral sequelae of severe malaria. Aim 3 is to identify the metabolic, immunologic and parasitic factors predictive of long-term neurobehavioral and functional impairment after severe malaria. We predict that severe malaria-related NBI will persist into adolescence and young adulthood, leading to substantial societal and economic costs, and that a number of risk factors for impairment will be detectable only as the child gets older and can be tested for higher level skills. Identification of risk factors present at a young age will allow for early intervention. We expect the study will constitute a major advance in the understanding of the neurobehavioral, functional and socioeconomic costs of severe malaria, and form the basis for focused interventions that can prevent or decrease neurobehavioral impairment in the millions of children who suffer from severe malaria.